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Abdel-Rahman, Sherif
The
focus of Dr. Abdel-Rahman’s research is on understanding how
inherited genetic characteristics influence the susceptibility of
individuals to environmental agents and affect the response to drug
therapy. Understanding of these processes will ultimately help
identify individuals who may be highly susceptible to the adverse
health effects resulting from environmental or occupational
exposures. In clinical settings, this will help to better predict
individuals’ response to drug therapy. Two complementary lines of
research are being pursued in his laboratory. The first involves
population studies using molecular epidemiology approaches and
focuses on developing methods to better identify individuals at high
risk of cancer and other adverse health effects associated with
environmental and occupational exposures using a battery of
biological markers for susceptibility, exposure and effect. The
second involves mechanistic studies using cell culture systems and
laboratory animals to understand the functional significance of
human genetic polymorphisms in susceptibility genes, and to study
the mechanisms of toxicity and carcinogenicity of environmental
chemicals.
Albrecht, Thomas
The major interests of Dr. Albrecht’s group are the
cellular response to genotoxic insults and the influence that
persistent human viruses have on these cellular responses. The
central hypothesis is that human cytomegalovirus (HCMV) infection
compromises cellular responses to genotoxic insult and thus
increases the sensitivity of persistently infected cells to genetic
damage. Of particular interest is how the cellular signaling
provoked by exposure to genotoxic chemicals or radiation influences
posttranslational modifications of regulatory proteins, activation
of specific proteases, and cell cycle entry and progression. For
example, the group is presently examining signaling pathways and
consequential events of environmentally significant genotoxins that
have contrasting effects on the cell cycle. Even though p53 and p21Cip1
are up-regulated by these chemicals, the effects on cell cycle
progression are quite distinct. Cellular responses are being studied
by cell cycle analysis, Northern and Western blotting,
immunofluorescence and confocal microscopy, immunoprecipitation, 2-D
gel electrophoresis, EMSAs, protein purification, kinase assays,
zymograms, null cell analysis and other techniques. HCMV is a
herpesvirus that persists in a number of organs with high indices of
cancer. HCMV induces modest levels of genetic damage, but, more
importantly, has been shown to synergistically increase the
sensitivity of cells to genotoxins such as bleomycin, MNNG, HAQO,
and tobacco smoke. Among the effects of HCMV on cellular responses
to genotoxic insult is activation of the ubiquitous cellular
calpains and degradation of p21Cip1, compromising
cell-cycle checkpoints. Analyses of virus effects have used
conditional infections, quantitative UV-irradiation, expression
vectors, and various measures of the level of HCMV expression and of
the viral effects on cellular parameters. Overall, this research has
provided new insights into processes that regulate the sensitivity
of cells to genotoxic damage and defined new interactive risk
factors.
Ansari, G.A. Shakeel
The major goal of Dr. Ansari’s research is to
elucidate molecular mechanisms of toxicity of halogenated
hydrocarbons, amines, unsaturated hydrocarbons and aldehydes.
Covalent binding to lipid and proteins is being studied as potential
mechanisms of toxicity. Dr. Ansari has shown that xenobiotics can
covalently modify fatty acids. Xenobiotics which are metabolized
through free radicals, bind to the unsaturated part of fatty acids,
while xenobiotics which contain hydroxyl or amino groups conjugate
at the carboxylic end of the fatty acids. These fatty acid
conjugates can cause selective organ toxicity which may be different
form the parent compounds. Dr. Ansari’s research has demonstrated
that the formation of fatty acid conjugates is an enzymatic process.
Organs most active in forming fatty acid conjugates are the liver
and pancreas. Characterization of the enzymes responsible for this
reaction in liver and pancreas indicated the enzymes belonged to the
carboxyesterase family. Two aspects of the adduction of
environmental chemicals to proteins are of interest. First,
adduction to circulatory proteins is examined in order to identify
biological markers of exposure. Second, adduction to cellular
proteins is being investigated as a mode of potential toxicity.
Cellular protein adducts have the potential to act as neoantigens
which stimulate autoimmunity and may ultimately cause autoimmune
diseases. Current studies are investigating the biotransformation of
the persistent environmental chemical trichloroethene to the
reactive metabolites trichloroethene oxide and dichloroacetyl
chloride, both of which can form protein adducts. A proteomic
approach is being used characterize to these tricholorethene-derided
adducts which are immunogenic.
Ansari, Naseem
Dr. Ansari has a long-standing interest in the role
of lipid-derived aldehydes (LDAs), the reactive and cytotoxic end
products of lipid peroxidation, in UV light-induced cataractogenesis
and retinopathy. Her research is based on the hypothesis that LDAs
extend oxidative injury in the lens and retina by causing
modifications to membrane proteins (including gap junction and
channel proteins), to membrane fluidity, and to calcium homeostasis
which result in apoptosis and thereby tissue damage. She is
investigating the metabolism of two LDAs, 4-hydroxynonenal and
4-hydroxyhexenal, in the ocular lens and retina under normal
physiological conditions and under oxidative stress. Her
results have demonstrated that the oxidative detoxification of HNE,
catalyzed by aldehyde dehydrogenase (ALDH), is most crucial in the
lens under conditions of oxidative stress. She has identified
ALDH1A1 as the isozyme which detoxifies HNE in the lens. Her studies
suggest that overexpression or activation of ALDH1 is anti-cataractogenic,
therefore in collaboration with Dr. Fox she is crystallizing the
human lens ALDH1A1 to develop structure-based activators of lens
aldehyde dehydrogenase-1.Techniques used include HPLC, gas
chromatography-mass spectroscopy, and electrospray ionization-mass
spectroscopy. By overexpressing LDA-detoxifying enzymes such as a
relevant glutathione-S-transferase isozyme (which conjugates the
LDAs to GSH), aldehyde dehydrogenase (which catalyzes LDA oxidation)
and aldose reductase (which catalyzes LDA reduction) in various cell
lines, she is critically assessing the influence of LDA metabolism
on the abrogation of oxidative injury. The long-term goal of Dr
Ansari's research on the fundamental biochemical pathways involved
in the detoxification of LDAs by lens and retina is to obtain
provide critical insights into the mechanism s by which these
aldehydes propagate and mediate oxidative injury to the eye.
Awasthi, Yogesh
The research interests of Dr. Awasthi’s laboratory
focus on the role of glutathione S-transferases (GST) and the
related transporter RLIP76 in the detoxification and export of
xenobiotics and including chemical carcinogens that are prevalent in
the environment. GSTs catalyzes the conjugation of the electrophilic
toxicants to glutathione (GSH) resulting in formation of
GSH-xenobiotic conjugates. These conjugates or their metabolites are
transported out of cells to make the detoxification process
complete. Currently, there are two major projects in the Awasthi
laboratory. The goal of the first project is to elucidate the
structures, functions and physiological/pharmacological relevance of
various GST isozymes. The second project focuses on the mechanisms
of transport for xenobiotics and their GSH-conjugates. Dr Awasthi’s
laboratory has discovered several new GST isozymes which are the
members of GST “supergene family” .and shown that GSTs have at least
three roles in negating the toxicity of xenobiotics. Besides
detoxifying electrophilic compounds, GSTs also protect cells from
the oxidative stress due to generation of ROS during the phase I
metabolism of xenobiotics by Cyp450. Specifically, his recent
studies have shown that in various cell types GSTA1-1 and GSTA2-2
protect cells against the deleterious effects of lipid peroxidation
initiated by ROS and from stress-mediated apoptosis. Furthermore,
GSTA4-4 protects cells not only from the oxidant xenobiotics but
also from stress induced-apoptosis. Thus, investigations that
coalesce the pharmacologic (detoxification of xenobiotics) and the
physiological (protection against lipid peroxidation and regulation
of signaling) roles of GSTs are ongoing in his laboratory. Dr.
Awasthi’s laboratory has shown that RLIP76, previously reported Ral
binding protein, is identical to the novel, non-ABC transporter,
DNP-SG ATPase previously discovered by his group. His group has
shown that RLIP76 is the major transporter of the GSH-conjugates of
xenobiotics as well as endobiotics, such as HNE which is a
regulatory small molecule in cell cycle signaling. These studies
have demonstrated that RLIP76 together with GSTA4-4 play an
important role in the regulation of cell cycle signaling,
particularly the pathways leading to apoptosis and/or cell
proliferation.
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B
Boor, Paul
The
laboratory of Dr. Boor is interested in how the larger blood vessels
of the body are injured by toxic chemicals in our environment. Focus
in on injury to the muscular wall of these blood vessels, or the
“media.” Experimental drugs and other chemicals that protect against
such injury –or predispose to injury – are under investigation in
the hope that someday we may be able to manipulate the blood vessel
wall to delay the commonest degenerative diseases that result in
great human morbidity and mortality, including atherosclerosis and
aneurysm. Specifically, Dr Boor’s laboratory has been defining the
cellular and biochemical events that occur during vascular injury by
toxic chemicals that are relevant to the environment, or to
cigarette smoke components. Past emphasis has been on the metabolism
of vasculotoxic amines to aldehydes, while recent work has defined
how glutathione-S-transferases act in the defense of vascular wall
against reactive molecules both in vivo and in vitro. Important
contributions to the understanding of the role played by coronary
arterial vasospasm in myocardial injury have been made. The role of
these defense mechanisms during cellular injury of the vascular wall
by atherosclerosis has also been recently examined. New directions
have been undertaken into the area of “developmental vasculotoxicity.”
Perhaps the most exciting new direction of the laboratory has been
the very recent development of a model of dissecting aortic
aneurysm. Initial studies into this small animal model have revealed
several pathways of fibrillogenesis of collagen and elastin that may
prove to be targets of toxic insult early in life, or even during
embryologic development, resulting in this deadly disease which is
just now coming to be recognized as a common killer of young
persons. Hence, Dr Boor’s studies delve into the most basic
phenomena underlying aging, aneurysm formation, and the
atherosclerotic process.
Braiser, Alan
Research by Dr. Brasier addresses a central problem
in cellular biology, namely how cells transduce signals in the
extracellular environment to produce long-lasting changes in the
expression of appropriate genes. Extracellular signals, taking the
form of hormones or environmental signals [such as reactive oxygen
species (ROS)] alter signal transduction pathways that ultimately
result in the activation of a limited set of DNA-binding proteins.
These transcription factors, in turn, activate expression of genetic
networks that play a dominant role in cellular response to stress
and the pathobiology of numerous human disease states including
accelerated atherosclerosis and asthma. Dr. Brasier’s laboratory has
concentrated on determining mechanisms of genetic responses to
inflammatory hormones in the cardiovascular and the respiratory
epithelium using cellular models that mimic the stereotypic response
of these tissues to more complex environmental toxicants. For
example, pulmonary cytokine cascades are elicited upon exposure to
inhaled toxicants, such as the oxidant ozone, and in response to
acute respiratory virus infection. Dr Brasier’s major goal has been
to define the mechanism for gene expression control by the nuclear
factor-B (NF-B) transcription factor, a latent cytoplasmic
protein. His work demonstrates that multiple extracellular stimuli
converge on this transcription factor through diverse intracellular
signaling pathways, activating it in multiple different ways.
Although in many cases these stimuli induce proteolysis of the NF-B
inhibitors (IB), releasing cytoplasmic NF-B to translocate into
the nuclear compartment, alternative redox sensitive pathways also
play important roles. In contrast to the conventional thought that
once liberated from its inhibitor, the NF-B protein was active, his
group has recently discovered that a separate ROS pathway is
activated that induces specific serine phosphorylation of the
transactivating NF-B Rel A subunit. Inhibition of this ROS pathway
does not prevent translocation, but activation of target genes.
Another area of current investigation is the novel recent finding
that waves of NF-B dependent gene expression are induced after its
nuclear appearance. Chromatin immunoprecipitation assays are being
conducted to determine the differences in promoter binding between
the various NF-B transcription factors and the coactivators
responsible for gene activation. Understanding how inflammation is
produced by ROS-NF-B pathway provides insight into how many
environmental agents produce common human diseases, and designing
better treatments to prevent these diseases.
Brooks, Edward
Dr. Brooks’ research examines the toxicological
effects of environmental agents on the immune system. The goal is to
elucidate the mechanisms by which insults induce exacerbation of
children’s asthma and developmental immune deficiencies. Since the
prevalence of asthma is widely increasing both nationally and
internationally—including 15 million Americans—such research is
important to understanding the etiology of the disease and to
developing effective therapies for its control. Dr. Brooks is
currently involved in characterizing proteins and their interactions
with IgE and cells involved in the allergic response as a basis for
understanding and treating diseases caused by exposure to
environmental pollutants, including allergic rhinitis and asthma.
The central hypothesis of his research is that oxidant pollutants
activate mucosal mast cells and thereby indirectly exacerbate
allergic responses. Questions addressed are important to our
country’s grappling with the setting of permissible exposure levels
for ozone, since the vast majority of research conducted has looked
for direct effects upon human health rather than those accomplished
indirectly. Ozone exposure is a significant problem for our local
Galveston-Houston area, where the number of days when ozone levels
exceed permissible levels alternates with Los Angeles for the
dubious distinction of highest in the nation. A major source for the
local environmental oxidants, including ozone, and volatile organic
compounds such as 1,3-butadiene and benzene, is the petrochemical
industry. Dr Brook’s research group uses a correlational
epidemiological approach to determine if ambient levels of these
environmental pollutants exert a direct health effect, specifically
exacerbation of children’s asthma. A long-standing project of Dr.
Brook’s is the impact of exposure to environmental agents upon
thymic development during gestation. Conducted in a mouse model,
this project has revealed that retinoic acid has profound
toxicological effects on the developing immune system by altering
the ability of the T-cell receptor loci to efficiently recombine,
resulting in abnormal T-cell repertoires and immune deficiency. A
current extension of this project is to develop ex vivo thymic
organoids on 3-dimensional tissue scaffolds. An intended application
of this unique model system is to investigate the impact of
environmental agents on T-cell development.
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C
Cheng, Xiaodong
The
major research focus in Dr. Cheng’s laboratory is function and
regulation of protein kinases and small GTPases in cancers. He is
also trying to understand the molecular mechanism of oncogene
RAS-mediated tumorgenesis and the effect of environmental insults
such as oxidative stress on cell transformation using genetically
defined cancer models and functional proteomics approaches.
Currently, there are three independent but closely related projects
in his laboratory. The first two are related to intracellular
signaling mediated by cAMP. cAMP-dependent protein kinase (PKA)
isoforms play different roles in regulating various cellular
processes, such as cell growth and differentiation. The linkage
between certain PKA isoforms and cancer has also been firmly
established. However, the underlying biochemical and structural
principles for isoform-specific PKA functions are not clearly
understood. To bridge this gap in our understanding, Dr. Cheng is
investigating the structure and function of different PKA isoforms
using biochemical, molecular and cellular approaches. He is
applying chemical-genetic and functional proteomic approaches to
determine the cellular substrates of different PKA isoforms.
Recently, a family of novel intracellular cAMP receptors, Exchange
proteins directly activated by cAMP (Epac), has been discovered. The
finding of a second intracellular cAMP receptor in addition to PKA
suggests that some, or even the majority of cAMP actions described
in the vast cAMP literature, do not act through the activation of
PKA alone, as previously believed. Therefore, dissecting the
functional roles of Epac in the overall cAMP-mediated intracellular
signaling is another current project of the Cheng lab.
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E
Elferink, Cornelis
The
major focus of Dr. Elferink’s research is the role of the aryl
hydrocarbon receptor (AhR) in liver homeostasis, with an emphasis on
the AhR-mediated regulation of cell cycle control and apoptosis. The
AhR is a ligand-activated soluble transcription factor historically
studied for its role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD,
dioxin) induced toxicity. TCDD toxicity however, represents a
disruption of normal AhR functions that influence fundamental
physiological processes underlying growth and differentiation. Dr
Elferink has found by studies in liver cells that the AhR, in
association with the retinoblastoma tumor suppressor protein,
regulates both passage through G1 phase of the cell cycle and
predisposes hepatocytes to Fas-mediated apoptosis. His long-term
objectives are to garner a mechanistic understanding of AhR activity
in liver regeneration following hepatic injury. These studies hold
the promise of identifying new therapeutic targets for the treatment
of various liver diseases such as hepatitis, cirrhosis and
hepatocellular carcinoma.
Englander, Ella
Mechanisms for repair of oxidative DNA damage in the
mammalian brain is the major research interest of Dr. Englander.
Cerebral hypoxia/ischemia as well as acute exposures to toxic
chemicals, such as combustion smoke, generate excessive oxidative
stress in the brain and lead to formation of free radicals, which
damage macromolecules, including DNA. Accumulation of oxidative DNA
damage in the human brain is implicated in the etiology of
posttraumatic and age-associated declines in neuronal function. Most
oxidative DNA lesions are repaired via the Base Excision Repair (BER)
pathway, which is a stepwise process initiated by aberrant base
removal by the DNA glycosylases. Dr Englander investigates the BER
pathway and oxidative DNA damage as a direct measurable result of
excessive oxidative stress in the brain. Also investigated are DNA
damage signaling, activation of genes involved in DNA damage
response, and correlations of their expression with cell survival or
cell death in the brain. Her goals are to understand the
relationship between the free radical-induced DNA damage, the
capacity for DNA damage repair and neuronal survival and, whether
the DNA repair response in the brain is consequential to
preservation and survival of neurons.
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G
Garofalo, Roberto
The major research interests of Dr. Garofalo’s
laboratory are the pathogenesis of respiratory syncytial virus (RSV)
infection and environmental risk factors for RSV infection. This
virus is the single most important viral pathogen causing acute
respiratory-tract infections in infants and children worldwide. In
addition, RSV-induced severe lower respiratory tract infections (bronchiolitis)
in infancy have been linked to both the development and the severity
of chronic asthma. A vaccine for RSV has yet to be developed and
immunity to natural infection(s) is incomplete, thus repeated
attacks of acute respiratory tract illness, ranging from common
colds to pneumonia, affect every individual through adulthood.
Although premature infants and those with certain underlying medical
conditions are predisposed to more severe infections, the majority
of infants hospitalized because of serious RSV disease are born at
term and otherwise healthy. This has suggested that risk factors,
other than those medical-related, are implicated in the pathogenesis
of bronchiolitis. In this regard, exposure to environmental tobacco
smoke (ETS) may occur in up to 60% of the infants with RSV
bronchiolitis in the US, and different studies have pointed to ETS
as a major risk factor for the development of severe infection. Dr.
Garofalo’s laboratory has shown that early inflammatory events
characteristic of the “innate” host response are crucially involved
in the pathogenesis of acute RSV-induced disease. One elements of
the innate immune system is the airway epithelial cell, which is the
major target of RSV infection. RSV-infected airway epithelial cells
produce a wide variety of regulatory molecules, known as cytokines,
which initiate and sustain immune and inflammatory responses in
airway mucosa. Therefore, a central hypothesis of Dr. Garofalo’s
research is that that exposure to tobacco smoke exacerbates airway
disease by enhancing or modifying the pattern of production of
cytokines and other immunomodulatory and/or inflammatory protein
mediators triggered by viral infection. Overall, these studies have
important implications for understanding the molecular mechanisms by
which biological agents and chemical pollutants interact, leading to
the development of asthma and other chronic airway diseases.
Goldblum, Randall
Dr. Goldblum's research focuses on the effects of
environmental factors on the immunologic processes that underly the
allergic respiratory diseases, especially asthma. The prevalence of
these diseases is increasing in developed countries, with up to 30%
of the population affected. In our region, an estimated 8-10% of
children have been diagnosed with asthma. Since the most dramatic
increases in asthma have occurred in industrialized countries, a
causative role for environmental pollutants has been suggested.
Recent novel observations by Dr. Goldblum's group suggest that the
expression of some pollen allergens is enhanced by environmental
stresses on the pollinating plants. Thus, allergenicity of the
pollen from plants grown in polluted environments may be increased,
leading to more allergic sensitization and symptoms. To test this
hypothesis, he is leading a study to determine the effects of
environmental factors, including ozone and UV light, on the
expression of a pathogenesis-related protein, Jun a3, of the
mountain cedar trees, a major source of seasonal allergic disease in
several regions of the world. In order to better understand the
structural requirement for proteins to serve as allergens, Dr.
Goldblum is also collaborating with a group of investigators,
including allergist and molecular biologists (Midoro-Horiuti)
structural biologists (Czerwinski, Braun and Schein) and cellular
immunologists (Brooks) to define the atomic features of allergens
and their importance in the allergic response. These studies include
molecular modeling and X-ray crystallography of cedar allergens;
immunochemical mapping of epitopes and cellular models of the
interaction of the allergens, specific IgE antibodies and mast
cells. By comparing the molecular structures of closely and more
distantly related allergen, they hope to define critical features of
allergens that can be used to develop vaccines that will prevent
common allergic reactions, including asthma. This collaboration
recently achieved a major goal the resolution of the crystal
structure of allergen Jun a 1 which as was published this year in
the Journal of Biological Chemistry. As Director of the Child Health
Research Center (CHRC) at UTMB, Dr Goldblum has been able to develop
an academic, scientific environment in which students at all level
of training (high school to junior faculty in Pediatrics) can
perform state-of-the-art research under the mentorship of highly
committed and productive senior scientists.
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H
Halpert, James
The major research interest of Dr. Halpert’s
laboratory is the mammalian cytochrome P450 system. These enzymes
constitute a superfamily of hemoproteins that play a pivotal role in
the metabolism of a wide variety of foreign compounds including
environmental contaminants, carcinogens, and drugs. Dr. Halpert’s
research focuses on elucidating the structural basis for the
catalytic specificity of individual P450 enzymes of the 2B and 3A
subfamilies. The central hypothesis of the research on 2B enzymes is
that substrate specificity reflects the interplay between amino acid
residues in the interior of the active site and those that line the
substrate access channel. This is being tested by a combination of
site-directed mutagenesis, directed evolution, functional assays, 3D
molecular modeling, and x-ray crystallography. Recent structures of
P450 2B4 in the absence and presence of inhibitor have revealed a
large conformational change upon ligand binding. Overall, the
studies on 2B enzymes are providing new insights into the specific
interactions of cytochromes P450 with ligands, and should have
fundamental implications for improving drug discovery and therapy,
safety assessment of chemicals, and individual risk assessment upon
exposure to xenobiotics. Research on P450 3A enzymes focuses on the
human enzyme P450 3A4. This is the most highly expressed P450 in the
liver of most humans, is responsible for the metabolism of more
clinically used drugs than any other P450, and is the locus of
numerous drug-drug interactions. Furthermore, P450 3A4 often
exhibits atypical kinetics, including positive homotropic
cooperativity, substrate inhibition, positive heterotropic
cooperativity, and partial inhibition. The central hypothesis is
that atypical interactions between two 3A4 substrates reflect
simultaneous occupancy of two or more preferred locations within a
single large binding pocket. This is being tested by a combination
of site-directed mutagenesis, functional analysis, high-pressure
perturbation spectroscopy, fluorescence resonance energy transfer,
and 3D molecular modeling. Results to date have provided compelling
evidence that P450 3A4 has discrete sub-pockets for the binding of
different ligands and may also exist as discrete conformers.
Knowledge of the molecular basis of P450 3A4 function should allow
the prediction of substrates, activators, and inhibitors, making it
possible to minimize drug-drug and drug-toxicant interactions and
interindividual differences in xenobiotic metabolism.
High, Karin Westlund
The ultimate goal of studies in Dr. Westlund-High’s
lab is development of treatment modalities for the chronic pain
caused by pancreatitis. Patients with pancreatitis or pancreatic
cancer complain of severe abdominal pain that is resistant even to
morphine. One animal model developed in Dr. Westlund-High’s lab,
with blood values and histology indicative of pancreatitis, involves
tail vein injection of a chemical agent, dibutyltin dichloride. The
biological effects of dibutyltin dichloride are typical of
intermediate organometals reported in the literature, including
deleterious effects on nerve endings and internal organs. Pancreatic
inflammation and behavioral changes develop that parallel the
decreased physical activity and malaise of cancer patients with
histological findings including edema, infiltration of blood cells,
widening of the ducts and acinar cell proliferation specific to the
pancreas. A chronic pancreatitis model is under development in which
young rats are fed a high fat and alcohol liquid diet. Pain-related
behaviors develop within two weeks and persist through at least
eight weeks. The pancreas additionally has fibrosis along with edema
and infiltration of blood cells. A collaborative analysis of fMRI
imaging revealed that the higher brain centers activated by the
inflamed pancreas are the brain centers found by anatomical studies
to be directly innervated by visceral pain pathways recently
discovered in Dr. Westlund-High’s lab. Activation is reversed by
morphine, naloxone blocked the morphine effect, and activity is
confirmed with electrophysiological recordings. These models of
toxicant-induced pancreatitis will be examined by fMRI imaging with
gene therapy approaches to opiate delivery for pain control. A viral
vector overexpressing the endogenous opiate, enkephalin, provides
restoration of open field behavioral activity and reduction of
hypersensitive responses confirming the efficacy of this therapy.
Novel non-mu opiate analogs that are currently being synthesized by
collaborator Dr. Scott Gilbertson, will be studied for effectiveness
in this model system. These studies will provide fresh insight into
how sensitization of this newly described pathway can lead to
persistent visceral pain states and how these pain states can be
alleviated.
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K
Kanz, Mary
Research in Dr. Kanz’s laboratory focuses on the
mechanisms by which environmental chemicals disrupt site and
cellular-specific processes in the biliary system. A central
hypothesis being tested is: Biliary toxicity starts with exposure to
reactive metabolites that are excreted into bile. Her laboratory has
shown that methylene dianiline (DAPM), a chemical used in the
manufacture of polymers and a known human hepatotoxicant, causes
selective injury to epithelial cells (BEC) of the intra- and
extrahepatic bile ducts, the structures which move bile out of the
liver, via the biliary route. Electron microscopic examination of
BEC indicates that mitochondria are an early site of injury
following DAPM administration. To investigate mechanisms of injury,
her laboratory has developed a novel in vitro model in which primary
cultures of rat BEC are exposed to bile collected from
toxicant-treated animals. Using this model, her laboratory has shown
that, following BEC uptake of [14C]-DAPM metabolites from
bile, deleterious effects are observed on mitochondrial membrane
potentials and ATP levels, plasma membrane glucose transport
functions and tight junction integrity. Studies characterizing and
quantifying DAPM metabolites in bile by high performance liquid
chromatography, and mass spectroscopy have identified possible
glutathione and glucuronide conjugates. Because these conjugates are
predominantly excreted into bile via the canalicular multispecific
organic anion transporter (cMOAT or Mrp2), DAPM injury is being
studied in transport-deficient [TR¯] rats which lack Mrp2. In TR¯
rats, DAPM injury is shifted from BEC to hepatocytes, suggesting
that export by Mrp2 transporter is a critical element in the biliary
injury induced by DAPM. Further studies that examine DAPM toxicity
after modulation of cMOAT activity are needed to confirm this
relationship. Although biliary diseases are prevalent in society and
have been linked to environmental chemicals, animal models of
biliary toxicity are extremely limited. The model systems developed
in the laboratory of Dr. Kanz address this limitation.
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L
Lu, Lee-Jane
The main research interest of Dr. Lu’s laboratory is
translational preventative medical research in humans. Her major
focus is breast cancer with a secondary interest in bone health.
Breast cancer take 20-30 years to develop. Therefore, prevention is
the most effective way to reduce the incidence of this disease.
Major risk factors for breast cancer revolve around ovarian hormones
and possibly other un-explored factors. Environmental factors play a
significant role in the etiology of breast cancer directly and
indirectly by modifying hormonal signalling. Dr. Lu’s breast cancer
prevention programs have two major focuses: 1) on the role of soy
diet, phytoestrogens, environmental estrogens, phytochemicals, and
nutrients on reproductive endocrine functions, immune responses, and
oxidative stress and 2) on the development of biological markers in
sera and nipple aspirate fluids for early detection, risk assessment
and prevention of breast cancer. These studies utilize clinical
investigation tools, state-of-the-art proteomic and genomic
approaches, epidemiologic and statistical tools, immunological
techniques, radiological imaging techniques (mammography, magnetic
resonance imaging), and image analysis tools. Specific topics
include investigation of factors: influencing bone and breast
density; metabolism and disposition of xenobiotics, phytochemicals,
and environmental chemicals; and the influences of nutrients on
cytokines, oxidative stress, and ovarian steroids.
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M
Mitra, Sankar
The central theme of Dr. Mitra’s research is
elucidation of the mechanisms for repair and regulation of DNA
lesions in mammalian cells which are generated either endogenously
or induced by reactive oxygen species (and ionizing radiation) or by
alkylating agents that produce DNA interstrand crosslinks. Thus, the
major focus of this research is base excision repair regulation,
although crosslink repair is also of interest. Dr. Mitra’s research
utilizes various molecular and cell biology tools. Particular
emphasized are: recombinant DNA techniques including the cloning of
the repair genes and their regulatory elements; gene targeting in
somatic and stem cells; gene overexpression; and the structural and
enzymological characterization of recombinant repair proteins.
Specific topics include the etiologic role of endogenous DNA damage
in apoptosis and signaling, covalent modifications of repair
proteins, and the linkage of preferential repair transcription and
DNA replication.
Moslen, Mary Treinen
Research by Dr. Mary Treinen-Moslen focuses on
consequences of protein adduction by xenobiotics that are
bioactivated to semi-stable reactive metabolites which cause injury
at distant sites. The xenobiotics investigated are the plasticizer
1,1-dicloroethylene and the pharmaceutical agent diclofenac, which a
widely used nonsteroidal anti-inflammatory drug [NSAID]. Both
xenobiotics are documented environmental pollutants. A recent
collaboration with a colleague at Vanderbilt demonstrated that the
selective bile canalicular injury by reactive glutathione conjugates
of 1,1-dicloethlyne is associated with alterations in the biliary
proteome. Collaborative studies with colleagues at NIH and NYU have
yielded strong circumstantial evidence that a causal factor in
diclofenac injury to the small intestine is formation of
drug-protein adducts by its reactive acyl-glucuronide metabolites.
These metabolites are formed in hepatocytes, transported across the
canalicular membranes via the MRP2 exporter, and delivered to the
intestine via bile. Small intestinal injury by NSAIDs, referred to
as NSAID enteropathy, is typically found in about 40 percent of
arthritics and others on chronic therapy with classical NSAIDs
[e.g., naproxen, diclofenac]. Little is known about either the
mechanistic basis of NSAID enteropathy or strategies to prevent this
problem. Dr Treinen-Moslen’s research team is addressing these
clinically relevant unknowns using a variety of approaches. Tissue
and cellular localization of the adducts is achieved by
immunohistochemistry with light, EM and confocal microscopy. Protein
targets of adduction are identified by Western blots, 2-D gels, and
proteomics. Injury associated changes in gene expression are sought
by found by microarray analysis of RNA obtained from defined sites
by laser capture microdissection. Agents that modulate the
enteropathy are used to probe likely events in the pathogenesis.
Mrp2 deficient rats are used to discriminate effects of this
important exporter on sites of diclofenac adduction. Long term goals
are to document adduction as a mechanism of enterocyte injury by
diclofenac and then to apply this information to the development of
safer regimes of NSAID therapy.
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Papaconstantinou, John
Currently, there are two major research programs in
laboratory of Dr John Papaconstantinou. The first, one of four
projects in his NIA Program Project “Oxidative Stress, Mitochondrial
Dysfunction and Aging” investigates the effects of aging on stress
response signaling pathways. Research addresses the proposal that
excess amounts of reactive oxygen species [ROS] in aged tissues,
produced by mitochondrial dysfunction, affect the function of the
p38 MAPK stress response. In support of this proposal, his
laboratory has shown age-associated modifications of the p38 MAPK
proteins (phosphorylation/cargbonylation) in aged mouse livers that
affect their kinase activity and docking. He has also shown that the
p38 MAPK pathway in the aged liver fails to respond to ROS caused by
mitochondrial dysfunction. This research program involves in-depth
analysis of molecular signaling mechanisms in aging tissues and
correlation of these processes with age-associated decline in tissue
function. The second program in Dr Papaconstatinou’s laboratory
involves identification of the molecular genetic processes that
control longevity in the long-lived mouse dwarf mutants (Snell dw/dw)
and Ames (df/df). These mice carry the Pit1 and Prop1 mutations,
respectively which results in GH deficiency and dwarfism. The goal
is to study whether the Pit1/Prop1 mutations result in a
reduction-of-function of the insulin/IGF-1 signaling pathway, and
whether this is a basic physiological factor that determines
longevity. Furthermore, he proposes to determine whether the Snell
and Ames dwarf mice mimic the physiological characteristics of the
long-lived nematode (C. elegans) daf-2 mutants, i.e., mutants
exhibiting a reduction of function of the daf-2 (insulin/IGF-1 like)
signaling pathway. The long range goal is to determine whether the
molecular genetics basis of longevity in the mice is similar to that
of the nematode.
Perez-Polo, Regino
Long-term goals of Dr. Perez-Polo’s research are to
understand the mechanisms of neuronal cell death and deficits
associated with aging, stroke, spinal cord injury and
oxidant-mediated environmental insults such as smoke inhalation. The
central hypothesis addressed is that oxidative stress triggers an
inflammatory response in CNS that compromises endogenous recovery. A
corollary hypothesis is that oxidative stress has genotoxic and
energetic consequences which activate stress response genes via
activation of NF-kB
transcription factor gene and repression of post-translational
modifications such as phosphorylation, protein degradation and
misfolding which result in the inappropriate organelle routing of
determinants for cell commitment to apoptosis or necrosis.
Transcription factors bind to cognate DNA sequences that regulate
the expression of stress response genes essential to survival and
function. Dr. Perez-Polo proposes that transcription factor binding
to cognate DNA sequences is finely tuned by the specificity of the
sequence, position within a promoter, and protein-protein
interactions with other sites on a promoter. Initial studies by his
laboratory have focused on choline acetyltransferase, IL-1b,
APE/Ref-1 DNA repair enzyme, Bcl-x genes, and the BACE-1 enzyme
responsible for the generation of b-amyloid. One consequence of
trauma to the CNS is the replacement of gene family expression
patterns present under normal homeostatic conditions by a
trauma-triggered altered phenotype. Key events following trauma are
aberrant neurogenesis and angiogenesis. For in vitro studies, his
laboratory uses the PC12 cell line and primary cultures obtained
from rat, mouse and guinea pig brain. For in vivo studies, his
laboratory uses MRI/MRS techniques to assess energy states in brain
and extent of cell death. Also used are reporter constructs and
transgenic models suitable to unraveling the role of the NF-kB
transcription factor in transcriptional regulation.
Petronella, Sharon
Dr. Petronella’s research focuses primarily upon
environmental epidemiological investigations of health effects
associated with exposures to air toxicants. She is participating in
several projects designed to elucidate the causes and mechanisms of
asthma exacerbations related to air pollution. One project is
investigating the effects of air pollution exposure upon a cohort of
105 lifeguards employed by the Galveston Beach Patrol. Parameters
evaluated in this interdisciplinary project include pulmonary
function, biomarkers for oxidative stress in exhaled breath, and
genetic polymorphisms in a glutathione S transferase detoxification
enzyme. This project, the Gulf Coast Study of Urban Air Quality and
Respiratory Function, has evolved into a model for translating a
community-based scientific study into public health and safety
interventions and policies. Another collaborative, interdisciplinary
project is investigating and developing interventions for effects of
the built environment upon asthma and childhood obesity. Dr.
Petronella serves as the environmental coordinator for a Texas State
Department of Health Services initiative to develop a state asthma
action plan. In addition, she is conducting a series of asthma
interventions in local area schools using her recently
standardized model for school indoor air
quality management in public schools.
Pikuleva, Irina
Research in Dr. Pikuleva’s laboratory focuses on structure/function
studies of four cytochrome P450 enzymes (P450s or CYPs) that
catalyze the first and key steps in cholesterol degradation in
mammals and, based on her new observations, may also metabolize
xenobiotics. Locations of these four enzymes are: CYP7A1 in the
liver, CYP46A1 in the brain, CYP11A1 in steroidogeneic tissues, and
CYP27A1 in all other extrahepatic tissues. The four P450s bind
cholesterol with a high affinity but metabolize it to different
products and have significantly varied catalytic efficiencies of
cholesterol hydroxylation. Thus, her long-term goals include
establishing: 1) how cholesterol-metabolizing P450s (share ≤25%
sequence identity) bind the very same substrate, cholesterol, yet
produce a different product, and 2) what factors underlie their very
different catalytic efficiencies allowing CYP7A1 to metabolize 600
mg of cholesterol every day and CYP46A1 only 6-7 mg. In addition, Dr
Pikuleva recently discovered that physiological significance of
CYP46A1 may not be limited to cholesterol homeostasis. She found
that this enzyme has broad substrate specificity and metabolizes a
number of structurally diverse compounds, including different
xenobiotics, in an in vitro reconstituted system. Her new
observations suggest that brain CYP46A1 may play a role similar to
that of liver CYP3A4 which is well known to be one of the most
important xenobiotic-metabolizing enzymes in mammals. However,
further studies are needed to confirm these novel in vitro findings.
Methodological approaches utilized in Dr. Pikuleva’s laboratory to
study these cholesterol- and xenobiotic-metabolizing P450s include
heterologous expression in E. coli, site-directed mutagenesis,
assays of enzyme activity and substrate binding, computer modeling,
mass spectrometry and crystallographic methods. Knowledge gained
during comparative studies of four P450s will provide insight into
the maintenance of cholesterol homeostasis, lead to better
understanding of structure/function relationships in the P450
superfamily, and should help clarify how certain drugs and
environmental pollutants are metabolized in the brain.
Prough, Donald
The primary interest of Dr Prough’s research team is
the pathogenesis and treatment of secondary brain injury occurring
after traumatic brain injury, such as that suffered in motor vehicle
accidents. The specific focus is on the role of free ionic zinc in
the destruction of hippocampal neurons after TBI. The neurotoxicity
of zinc is tightly linked to the excitotoxicity of glutamate by two
processes: first, presynaptic glutamate release results in
presynaptic release of potentially toxic quantities of zinc which
enters cells through glutamate-receptor gated channels; and second,
zinc is released from intracellular metallothionein stores as a
consequence of generation of peroxynitrite from nitric oxide
synthesized after glutamate stimulation of N-methyl D-aspartate (NMDA)
receptors. Superoxide anion, also generated by traumatic brain
injury, is the other component necessary for generation of
peroxynitrite. His laboratory explores various physiologic and
pharmacologic methods for limiting zinc neurotoxicity, examines the
molecular correlates of those interventions, and determines the
influence of those interventions on neurobehavioral outcomes.
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Taglialatela, Giulio
The main interest of Dr. Taglialatela’s research
group is the cellular stress response in the aged or diseased
central nervous system (CNS). Specifically postulated is that
toxicants like cytokines, free radicals and amyloid beta (A)
trigger cellular stress responses that become maladaptive in the
aged or diseased CNS, thus leading to impairments of selected
neuronal species. The overarching goal is to systematically identify
molecular events leading to improper or maladaptive cellular stress
response in aged or diseased neurons in order to obtain fresh
insight into new strategies for preventing neurodegeneration. With
this goal in mind, Dr Taglialatela’s research group has identified
unique responses of nerve growth factor (NGF)-responsive cholinergic
neurons, a neuronal type severely affected in Alzheimer’s Disease,
that when challenged with pro-inflammatory cytokines selectively
up-regulate iNOS, thus undergoing cytotoxic oxidative stress. His
group has also found that oxidative stress in the CNS promotes
up-regulation of the typically anti-apoptotic protein Bcl-2. However
in oxidatively stressed aged neurons, Bcl-2 becomes atypically
localized in the nucleus where Bcl-2 could promote cell death rather
than protecting from apoptosis. Similar up-regulation of Bcl-2
expression associated with oxidative DNA damage and A plaques has
been reported in the neurodegenerating CNS of Alzheimer’s patients.
This exciting observations about atypical Bcl-2 localization in
oxidatively stressed aging neurons has prompted a focus on the
molecular mechanisms leading to nuclear association of Bcl-2 and the
consequences of the excessive presence of Bcl-2 within the nuclear
compartment, with particular regard to regulation of transcription
factor activity and cell apoptosis. The long term goal is to
modulate neuronal and cellular responses to extrinsic and intrinsic
toxicants so as to prevent or reverse the onset of associated
deficits.
Toliver-Kinsky, Tracy
The research in Dr. Toliver-Kinsky’s laboratory
focuses on the state of immunocompromise that is induced by trauma
from smoke inhalation or severe burn trauma. Injuries from severe
burn and smoke inhalation induce alterations in immune function that
leave patients susceptible to nosocomial infections that increase
morbidity and mortality. The main goals of her research are to
understand the mechanisms by which these injuries increases
susceptibility to infections, and to investigate immunomodulatory
strategies that may increase resistance to infections after trauma.
Current research efforts are focused on the use of a hematopoietic
cytokine and dendritic cell growth factor as a prophylactic
treatment after burn injury to stimulate the production of new
progenitor cells that give rise to dendritic cells. Dendritic cells
are antigen presenting cells that reside in tissues that frequently
encounter environmental pathogens, such as skin, airway, and
digestive tract. Recognition of microorganisms by dendritic cells
triggers responses that are central in the activation and regulation
of both innate and acquired immunities. Therefore, Dr
Toliver-Kinsky’s project is based on the hypothesis that stimulation
of dendritic cell production after smoke inhalation or burn injury
can increase resistance to infections with microorganisms that are
frequently encountered in the burn care environment. In vivo models
of experimental injury and infection are employed to assess local
and systemic responses by a variety of molecular, cellular,
microbiological and immunological techniques. By integrating
multiple aspects of whole animal biology, this project should
provide insight into the mechanisms by which smoke inhalation and
severe burn injury impact immune function and should provide the
rationale for immunomodulation after these injuries using
hematopoietic stimuli and immune cell growth factors.
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Ward, Jr., Jonathan
The
research of Dr. Ward addresses environmental health issues by
investigating the mutagenic effects of chemicals that are frequently
found in workplaces and communities. He is interested in the
mechanistic basis for mutations produced when humans are exposed to
low levels of chemicals. An additional aspect of his research is to
investigate how susceptibility to toxic chemicals is modified by
genetic polymorphisms in key genes controlling biotransformation
reactions. To accomplish this, he uses biological markers as
endpoints in human population studies. A major study is examining
the effects of occupational exposure to 1,3-butadiene, a known
carcinogen, by evaluating lymphocytes from workers in rubber and
petrochemical plants for the frequency of mutations in a reporter
gene (hprt) along with measures of exposure. Workers exposed to
about 1 ppm of butadiene (the current allowable exposure limit) were
found to have an increased frequency of mutations. The highest
mutation frequencies were found in a subgroup of workers carrying
polymorphic forms of microsomal epoxide hydrolase with predicted low
activity. Parallel experimental studies have determined that mice
exposed to low levels of butadiene by inhalation also experience
increases in Hprt mutant frequencies. Mice with a knockout mutation
that inactivates microsomal epoxide hydrolase were more sensitive to
the mutagenic effects of butadiene and its metabolites butadiene
monoepoxide and butadiene diepoxide. Characterization of the
mutation spectrums, using multiplex PCR and automated DNA
sequencing, indicated an elevation of deletion mutations in cells
from 1,3-butadiene exposed workers as well as mutations found in
mice and cultured cells exposed to butadiene and its metabolites.
Collectively, these observations suggest that current levels of
occupational exposure to butadiene might pose health risks,
particularly for workers with low activity polymorphisms in
microsomal epoxide hydrolase. In addition to his laboratory research
activities, Dr. Ward is the director of a community intervention
project, “Communities Organized against Asthma and Lead” which is a
partnership with a community organization, DeMadres a Madres, in
Houston, TX and a medical clinic. Homes in a predominantly Hispanic
community are being assessed for the presence of lead and asthma
triggers in order to reduce the exposures of children to these
hazardous agents. The overall goals of Dr Ward’ laboratory and
community-based research efforts are to improve understanding of the
hazards presented by genotoxic chemical exposures and the prevalence
of such hazards among communities.
Watson, Cheryl
Dr. Watson has a long standing interest in the
molecular mechanisms of action for estrogens and xenoestrogens.
Environmental estrogen mimetics are thought to mediate reproductive,
developmental and carcinogenic pathologies. These kinds of compounds
are known as “endocrine disruptors”. She has have recently shown
that sub-picomolar to nanomolar quantities of xenoestrogens can act
like a physiological estrogen (estradiol) to generate rapid
signaling sequellae (Ca++ elevation, ERK activation, cAMP
elevation) that lead to changes in cellular function (rapid release
of prolactin and other growth factors, proliferation). These
compounds can act via binding to a subpopulation of estrogen
receptors residing in the plasma membrane of pituitary tumor cells,
breast cancer cells, and other steroid-responsive cell lines
representing different tissues. The response patterns for individual
xenoestrogens differ both in dose-response and timing, perhaps
contributing to their ability to interrupt or inappropriately mimic
physiological estrogens. Dr Watson is using these models to further
dissect the signaling mechanisms of individual environmental and
nutritional estrogens. Her goal is improve understanding of the
mechanistic basis for environmental estrogen actions in order to
reveal fresh strategies for preventive and therapeutic
interventions. Recognition of mechanisms via which xenoestrogens can
have potent actions will contribute to the reevaluation of allowable
contamination levels and regulation of these compounds.
Weinman, Steven
Research in Dr. Weinman’s laboratory focuses on the
regulation of hepatocyte function and mechanisms of liver injury in
response to viral and environmental perturbations. Specific areas
under investigation include: 1) the role of mitochondrial injury and
oxidative stress in pathogeneisis of Hepatitis C and, and 2)
regulation of hepatocyte chloride channels in liver inflammation.
Hepatitis C is a common liver disease resulting from hepatocyte
infection with the HCV virus, an important toxicological concern
because infection with this virus is well established to sensitize
the liver to injury by alcohol. The mechanism responsible for this
sensitization, however, is unknown. Dr. Weinman’s research is
exploring the role of HCV-induced mitochondrial dysfunction and
oxidative stress in causing alcohol sensitivity. His group has shown
that the HCV core protein plays a major role in sensitizing
hepatocytes to environmental stresses. Core protein localizes to
mitochondria where it causes an inhibition of complex I electron
transport, an increase in ROS production and enhanced sensitivity of
the cells to exogenous peroxides and cytokines. Current studies are
looking at the role of ER-mitochondria interactions in these effects
and the ability of exogenous oxidative stress and antioxidants to
alter the progression of liver injury in this disease. In addition,
other research by Dr. Weinman has demonstrated that intracellular
chloride channels are required for transport of copper into
intracellular vesicles. Thus, he is also investigating the role of
chloride channels in modulating environmental heavy metal toxicity.
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Xie, Jingwu
A major focus of Dr Xie’s research is to identify
novel ways to prevent basal cell carcinoma (BCC), the most common
form of human cancer that is usually caused by ultraviolet light
exposure. BCC affects approximately one million Americans per year.
Basal cell carcinoma is now understood to be associated with both
somatic and germ line gene mutations in the sonic hedgehog signaling
pathway. Two major genes of the sonic hedgehog pathway are altered
in BCCs, namely, a functional loss of the Patched gene (PTCH1) and
activation of the smoothened (SMO) gene. Abnormal activation of this
pathway is also implicated in the development of medulloblastomas,
lung, prostate and GI cancers. SMO is a key signaling molecule whose
activity can be inhibited by the sonic hedgehog receptor-Patched.
However, most of the sonic hedgehog signaling pathway downstream of
SMO is unknown or poorly understood. Dr Xie addresses these unknowns
using cultured cells as well as mouse models. His goal is to improve
basic understanding of the hedgehog signaling mechanisms in his
established mouse model of BCC in order to develop novel strategies
for prevention or treatment of BCC. Specifically, he would like to
identify ways to inhibit the sonic hedgehog pathway with small
molecules in human BCCs. Because this pathway is involved in the
development of several types of human cancers, Dr Xie’s research has
significant clinical implications for treatment of hedgehog-driven
cancers.
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